Kaposi's sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is the most common cause of malignancies among patients with HIV/AIDS. To date, no effective therapies exist for these fatal cancers caused by KSHV. Recent studies indicate that the cellular transcription factor NF-kB plays critical roles in both KSHV-associated malignancies and HIV-associated AIDS, therefore providing an ideal therapeutic target for treating KSHV-mediated cancers, and in particular those associated with HIV/AIDS. However, human clinical trials show that it is impractical to block NF-kB activation for cancer therapy using classical NF-kB inhibitors because of the physiological importance of NF-kB in humans. The proposed studies in this grant application arise from our efforts to understand the molecular differences in the oncogenic and physiological activation of NF-kB as an approach to identify new therapeutic targets for NF-kB-associated cancers. In this regard, we have recently identified PDZ-LIM domain-containing protein 2 (PDLIM2) as a unique tumor suppressor that selectively suppresses pathogenic (constitutive) but not physiologic (transient) activation of NF-kB through terminating but not blocking NF-kB activation. Thus, PDLIM2-based therapy will effectively alleviate NF-kB- mediated oncogenesis and therapeutic resistance while keeping the physiological functions of NF-kB intact in patients. Interestingly, our preliminary dat show that the expression of PDLIM2 is epigenetically repressed in KSHV-transformed cells, and that expression of exogenous PDLIM2 prevents the oncogenic NF-kB activation and tumorigenicity of these malignant cells. Notably, endogenous PDLIM2 in KSHV-transformed cells can be restored by the epigenetic drug 5-aza-dC to suppress their abnormal growth, at least under in vitro culture conditions. Based on these innovative findings, we aim to (1) determine the association among the repression of PDLIM2 expression, DNA methyltransferase expression, pdlim2 promoter methylation, and NF-kB activation during KSHV infection and tumorigenesis, and (2) determine in vitro and in vivo the significance of PDLIM2/ NF-kB signaling in KSHV tumorigenesis and 5-aza-dC's cytotoxicity on KSHV+ cancer cells. These preclinical studies will determine the clinicopathological significance of PDLIM2/NF-kB signaling in KSHV tumorigenesis, and therefore greatly increase our understanding of KSHV-mediated diseases, particularly those associated with HIV/AIDS. These studies will also form a solid basis for our future studies to establish PDLIM2 epigenetic restoration as primary and adjuvant therapies for HIV/AIDS-associated malignancies caused by KSHV.